Although thyroxine (tetraiodothyronine; T4) is the principal secretory product of the vertebrate thyroid, its essential metabolic and developmental effects are primarily mediated by 3,3,5-triiodothyronine (T3), which is produced from the prohormone by 5′-deiodination. The type I iodothyronine deiodinase (D1), a thiol-requiring propylthiouracil-sensitive oxidoreductase, is found mainly in liver and kidney and catalyzes conversion of T4 to T3 by a deiodination reaction at the outer ring of T4 and conversion of 3,3′,5′-triiodothyronine (reverse T3, rT3) to 3,3′-diiodothyronine (T2). Two other deiodinases have also been described, type II deiodinase (D2) and type III deiodinase (D3). The action of D2 is similar to D1; however, D2 is primarily found in the thyroid, pituitary gland, brain, brown fat and testis. In contrast to D1 and D2, D3 functions exclusively as a 5-deiodindinase and catalyzes the conversion of T4 and T3 to inactive metabolites (rT3 and T2, respectively) and is primarily found in fetal tissues, placenta, skin and brain as well as brown and white preadipocytes. See Bianco, et al. (2002) Endocrine Rev. 23:38-89.
By targeted inactivation of the D3 gene in mouse embryonic stem cells, D3-knockout mice have been generated and shown to exhibit neonatal thyrotoxicosis followed later by persistent central hypothyroidism (Hernandez, et al. (2006) J. Clin. Invest. 116: 476-484). Early in life, the mutant mice have delayed T3 clearance, markedly elevated serum T3 levels, and overexpression of T3-inducible genes in the brain. From postnatal day 15 through adulthood, D3-knockout mice exhibit central hypothyroidism, with low serum levels of T4 and T3, and modest or no increase in thyroid-stimulating hormone concentration; peripheral tissues are also hypothyroid. Hypothalamic T3 content is decreased, whereas thyrotropin-releasing hormone expression is elevated. Furthermore, treatment of D3-knockout mice with T3 results in weight loss and lethality in mutant animals (Hernandez, et al. (2007) Endocrinology 148:5680-5687). Based upon these results, it has been concluded that D3 plays a critical role in the maturation and function of the thyroid axis.
D3 expression in a brown fat vascular-stromal (BVS-1) cell line has been shown to be regulated by growth factors such as EGF, acid or basic FGF, wherein preincubation of cells overnight with dexamethasone completely blocks the D3-inducing effects of basic FGF and decreased basal D3 activity by 80% (Hernandez & Germain (2002) Endocrinology 143:2652-2658). Similarly, acute or chronic treatment of neotenic axolotls (Ambystoma mexicanum) with dexamethasone has been shown to decrease hepatic and renal D3 activity in a dose-dependent manner, with all dexamethasone-treated axolotls showing a clear reduction in gill length, tail height, and body weight (Darras, et al. (2002) Gen. Comparat. Endocrinol. 127:157-164)